Akinori Nishikawa

Autologous hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission: outcomes before and after the introduction of arsenic trioxide

Abstract We conducted a retrospective registry-based study involving 198 patients with acute promyelocytic leukemia (APL) who underwent autologous hematopoietic cell transplantation (HCT) during second complete remission (CR2) from 1995 to 2012. Arsenic trioxide (ATO) became commercially available in Japan in December 2004, and a substantial increase in the annual numbers of transplantations has occurred since 2005. Patients transplanted after 2006 had significantly better relapse-free and overall survival than those transplanted before 2004 (p = .028 and p = .027, respectively). There was a significant difference in cumulative incidence of relapse in favor of those transplanted after 2006 (p = .008), whereas non-relapse mortality did not differ between the two groups (p = .683). Our findings suggest that the introduction of ATO may have reduced post-transplantation relapse without increasing non-relapse mortality, resulting in significant improvements in overall outcomes for relapsed APL patients undergoing autologous HCT during CR2.

A novel immunopathological association of IgG4-RD and vasculitis with Hashimoto's thyroiditis

Summary A 73-year-old man with Hashimotos thyroiditis (HT) suffered from purpura on the lower legs. He was diagnosed with IgG4-related disease (IgG4-RD) with serum IgG4 elevation and dacryo-sialadenitis confirmed histologically. Serum Th2 and Treg cytokines, interleukin 7 (IL7), IL8 and Th2 chemokine levels were elevated, while skewed Th1 balance was seen in fluorescence-activated cell sorting (FACS). Therefore, preferential Th1 balance in HT appeared to be followed by IgG4-RD characterized with Th2 and Treg polarization. The commencement of steroid therapy dramatically exacerbated clinical manifestations including IgG4-RD-associated HT. The measurement of cytokine and chemokine levels as well as FACS analysis in the development of IgG4-RD seemed to be beneficial. In conclusion, an innovative association of HT, IgG4-RD and vasculitis was observed. This report also offers novel diagnostic and therapeutic approaches for IgG4-RD. Learning points Recently, a subtype of HT has been considered to be a thyroid manifestation of IgG4-RD, although the etiology of IgG4-RD is not established yet. Immunologically a close association between HT and vasculitis was reported. Leukocytoclastic vasculitis is a rare skin presentation of IgG4-RD. In the current case, during the course of HT, IgG4-RD and leukocytoclastic vasculitis occurred; thus, innate immunity and acquired immunity seem to be involved in the development of IgG4-RD. The measurement of cytokine and chemokines appeared to be beneficial in the development of IgG4-RD. Remarkably, effectiveness of steroid therapy for HT suggested presence of IgG4-RD-associated HT. Therefore, this report highlights the pathogenesis of IgG4-RD and proposes novel therapeutic mechanisms. Clinicians should pay attention to the development of IgG4-RD and vasculitis during long course of HT.

Real-time monitoring of antimicrobial use density to reduce antimicrobial resistance through the promotion of antimicrobial heterogeneity in a haematology/oncology unit

BACKGROUND In haematology/oncology units, the frequent and heavy use of broad-spectrum antimicrobials can lead to outbreaks of antimicrobial resistance. Increasing antimicrobial heterogeneity might be a useful strategy for preventing such resistance. METHODS A real-time antimicrobial use density (AUD) monitoring system (RAMS) was developed to precisely assess antimicrobial heterogeneity. This study was prospectively conducted over a 39 month period and involved 970 patients. Patient-specific antimicrobial therapy with five carbapenems (meropenem, biapenem, panipenem/betamipron, imipenem/cilastatin and doripenem) and four non-carbapenems (piperacillin/tazobactam, ceftazidime, cefozopran and cefepime) was prescribed in the first 12 months. A first-line antimicrobial was selected from among nine antimicrobials according to a predetermined schedule for the next 15 months. AUD-based antimicrobial selection was implemented using the RAMS during the last 12 months. We compared our findings for the RAMS period with those for the other periods to determine the effects of RAMS-based AUD monitoring on antimicrobial resistance. RESULTS The mean absolute difference between the AUD values of carbapenems and non-carbapenems (AUD deviation) was 6.0% in the RAMS period (range 0.5%-15.8%) and antimicrobial heterogeneity (AUD deviation <10%) was achieved in 10 out of 12 months (83.3%). Furthermore, during the RAMS period, AUD deviation was significantly smaller and the frequency of outbreaks of antimicrobial-resistant strains other than Stenotrophomonas maltophilia was significantly decreased (from 7.9% to 3.5%; P < 0.01) compared with the other periods. CONCLUSIONS The longer period of stable antimicrobial heterogeneity achieved by the RAMS strengthened its preventive effects against antimicrobial resistance. Optimal antimicrobial heterogeneity based on real-time AUD monitoring could reduce the frequency of outbreaks of antimicrobial resistance.

Refractory Ascites with Liver Fibrosis Developed in Late Phase Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Patients.

We report cases of three patients of refractory ascites without other fluid retention that occurred around five months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). All three patients expired and postmortem examinations revealed unexpected liver fibrosis lacking histological evidences of graft-versus-host-disease (GVHD). The three patients showed normal hepatic function and size before transplantation. During their clinical courses, serum biochemistry test showed no elevation of hepatic enzymes and bilirubin; however, imaging studies demonstrated hepatic atrophy at the onset of ascites. One of the liver specimens showed bile obstruction, which could be seen in hepatic damage by GVHD. Although ascites resulting from venoocclusive disease in early phase allo-HSCT is well documented, ascites associated with hepatic fibrosis in late phase allo-HCST has not been reported. Further clinico-pathological studies on similar patients should be required to ascertain refractory ascites associated with liver fibrosis after allo-HSCT.

B-Cell-Rich T-Cell Lymphoma Associated with Epstein-Barr Virus-Reactivation and T-Cell Suppression Following Antithymocyte Globulin Therapy in a Patient with Severe Aplastic Anemia

B-cell lymphoproliferative disorder (B-LPD) is generally characterized by the proliferation of Epstein-Barr virus (EBV)-infected B lymphocytes. We here report the development of EBV-negative B-LPD associated with EBV-reactivation following antithymocyte globulin (ATG) therapy in a patient with aplastic anemia. The molecular autopsy study showed the sparse EBV-infected clonal T cells could be critically involved in the pathogenesis of EBV-negative oligoclonal B-LPD through cytokine amplification and escape from T-cell surveillances attributable to ATG-based immunosuppressive therapy, leading to an extremely rare B-cell-rich T-cell lymphoma. This report helps in elucidating the complex pathophysiology of intractable B-LPD refractory to rituximab.

Severe graft-versus-host disease after allogeneic hematopoietic stem cell transplantation with residual mogamulizumab concentration

We read with great interest the two articles by Tsubokura et al. and Ishitsuka et al. on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult T-cell leukemia/ lymphoma (ATLL) [1, 2]. Regimens containing mogamulizumab (Mog), an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, are expected to achieve good disease control before allo-HSCT and may result in low relapse rate after allo-HSCT. However, there is a concern that the use of Mog before allo-HSCT may cause severe acute graftversus-host disease (aGVHD), as Mog eradicates normal CCR4-positive cells, including regulatory T cells (Tregs). Fuji et al. reported that Mog administration is associated with significantly increased risk of severe aGVHD due to such reduction in Tregs [3]. At present, there is no consensus on how to use Mog before allo-HSCT in Japan. Recently, Tsubokura et al. reported that monitoring of Tregs was useful for avoiding severe aGVHD [1]. Ishitsuka et al. demonstrated that the interval between the last administration of Mog and transplantation affected aGVHD [2]. In addition to monitoring of Tregs and the interval of administration, Fuji et al. proposed that monitoring of serum Mog level in peripheral blood is warranted [3]. However, little is known about the association between serum Mog level, Tregs, and aGVHD at the moment, and the threshold of serum Mog concentration at allo-HSCT has not been established. Here, we report the clinical course of an ATLL patient in whom Tregs and serum Mog concentration were measured after allo-HSCT (Fig. 1). The patient was a 59-year-old man diagnosed with acutetype ATLL. He received chemotherapy, resulting in partial remission with residual abnormal lymphocyte in peripheral blood. He received 10 cycles of Mog (1 mg/kg) and achieved complete remission. He underwent unrelated bone marrow transplantation from HLA-C locus mismatched donor at 40 days after the last Mog administration in October 2012. He was given a reduced-intensity conditioning regimen, consisting of fludarabine, melphalan, and 2 Gy of total body irradiation. aGVHD prophylaxis was tacrolimus and short-term methotrexate. Engraftment was achieved by day 16 after transplantation. He developed grade II aGVHD (skin 3, gut 0, liver 0) at engraftment and given prednisolone (2.0 mg/kg/day). However, he developed diarrhea due to intestinal aGVHD and was administered mycophenolate mofetil on day 42. His serum concentration of Mog was 317.6 ng/mL. Tregs, which were identified as CD25-positive, CD127-negative cells, were counted as 4.1% in the CD4-positive T-cell gate. Total and CD4-positive lymphocytes at that time were counted as 153/μL and 11/μL, respectively. Because skin rush and diarrhea persisted, he received rabbit antithymoglobulin 1 mg/kg intravenously on day 48. The highest grade and stage of aGVHD were grade IV, skin 4, gut 3 and liver 0. He developed melena with decreased platelet count and elevated LDH due to thrombotic microangiopathy. His serum level of Mog was < 5 ng/mL on day 120 after allo-HSCT. Tregs increased to 31.5% in the CD4positive T-cell gate. Total and CD4-positive lymphocyte were 554/μL and 12/μL, respectively. He died on day 133 * Takashi Sonoki sonoki@wakayama-med.ac.jp

Long-term complete remission of early hematological relapse after discontinuation of immunosuppressants following allogeneic transplantation for Sezary syndrome

Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma and is chemo-resistant. Allogeneic hematopoietic stem cell transplantation is a promising therapy for SS; however, relapse is common. Therapeutic options after relapse have not been established. We managed an SS patient with hematological relapse within one month after transplantation. After discontinuation of immunosuppressants, she achieved complete remission and remained relapse-free. The chimeric analyses of Tcells showed that the full recipient type became complete donor chimera after immunological symptoms. This clinical course suggested that discontinuation of immunosuppressants may result in a graftversus- tumor effect, leading to the eradication of lymphoma cells.

An Epstein-Barr virus susceptible immature T-cell line, WILL4, established from a patient with T-lymphoblastic lymphoma bearing CD21 and a clonal EBV genome

We managed a patient with an Epstein-Barr virus-associated T-cell lymphoblastic lymphoma. Mediastinal tumor cells at initial admission were positive for CD4, CD8, and TdT. Interestingly, a lymph node at necropsy was compatible for a CD4-positive peripheral T-cell lymphoma without CD8 and TdT expression, suggesting a different phenotype from the mediastinal tumor. Tumor cells in pleural effusion continued to proliferate in in vitro and were designated as WILL4. WILL4 cells were positive for CD3, CD4, CD8, CD21, T-cell receptor (TcR) αβ, and TdT, indicating a similar phenotype to thymocytes. Southern blot analyses showed that the pleural tumor and WILL4 cells shared a TcR gene rearrangement, and that both contained a clonal EBV genome in an episomal form. RT-PCR showed that EBNA1 and LMP1 were expressed in the fresh tumor and WILL4 cells. Southern blot analyses revealed that WILL4 cells were susceptible to EBV infection in vitro using B95-8 supernatant. Anti-CD21 antibody inhibited in vitro infection of EBV, suggesting that CD21 plays a role in EBV infection into WILL4 cells. In vitro infection of EBV did not affect latent gene expression in WILL4 cells. WILL4 is a useful tool for analyzing the roles of EBV in onocogenesis in immature T-lymphoid malignancies.

An Optimal Approach for Fluoroquinolone Garenoxacin Prophylaxis in Patients with Hematological Malignancies and Chemotherapy-induced Neutropenia

Antibiotic prophylaxis such as that with fluoroquinolone reportedly reduces infectious episodes in patients receiving chemotherapy regimens with the risk of febrile neutropenia. However, optimum patient characteristics, the timing of initiation, and antibiotics for prophylactic treatments have yet to be identified. We herein conducted a single-arm monocenter clinical study to elucidate the therapeutic profiles of fluoroquinolone garenoxacin prophylaxis for patients with hematological malignancies (HMs). Fever was not present for the duration of chemotherapyinduced neutropenia in 29 (43.9%) out of 66 patients. A shorter duration of prophylaxis until chemotherapy-induced neutropenia had a more potent effect on delaying febrile episodes, even in patients with fever. Excessive neutropenia (minimum zero neutrophils/l) negatively affected prophylactic effects. Garenoxacin accounted for 4.5% of the minor adverse events observed such as mild renal damage and skin reactions. Therefore, the study suggests that the initiation of garenoxacin prophylaxis from the introduction of neutropenia could be an effectual strategy for preventing chemotherapy-induced febrile episodes in HM patients with moderate neutropenia.

Successful intrathecal chemotherapy combined with radiotherapy followed by pomalidomide and low-dose dexamethasone maintenance therapy for a primary plasma cell leukemia patient

Primary plasma cell leukemia (PPCL) is a rare aggressive variant of plasma cell disorder and frequently presents with extramedullary disease. Central nervous system (CNS) involvement with PPCL has an extremely poor prognosis. We describe a 46-year-old man with PPCL treated with a combination of lenalidomide, bortezomib, and dexamethasone as induction therapy following upfront allogeneic stem cell transplantation (allo-SCT). Despite achieving a very good partial response, the patient suffered from an isolated CNS relapse 12 months after allo-SCT. He was immediately started on concurrent intrathecal chemotherapy (IT) and cranial irradiation (RT). Subsequently, pomalidomide and low-dose dexamethasone (Pd) were given as maintenance therapy. He has been without CNS recurrence for more than 18 months. Our case suggests that concurrent IT and RT followed by Pd maintenance therapy may be an effective option to control CNS relapse of PPCL after allo-SCT.